Welcome to HostMicrobeLit, a blog for highlighting research in host-microbe interactions. This first post will be highlighting some excellent review reviews published in the field. (I’m going to try do a reviews post at least once every couple of months). This one will be a bit more Microbiome focused.
First up is an open access article in Gut containing two very big names in Microbiome research Willem de Vos & Patrice Cani.
Gut microbiome and health: mechanistic insights – de Vos et al. Gut. 2022
The article gives a great overview of current knowledge of how the gut microbiome interacts with the host, with a specific focus on microbially produced compounds (e.g. short chain fatty acids, bile acids). But it also digs into mechanisms often less discussed in the literature such as bacterial activation of the aryl hydrocarbon receptor, a transcription factor that regulates numerous genes involved in inflammation and immunity.
The article ends by highlighting the importantance for moving from correlation to causation in gut microbiome research.
The second review I want to highlight today is an article published in Nature Reviews Microbiology.
Microbiome-based therapeutics – Sorbara & Palmer. Nature Reviews Microbiology. 2022
Frankly an excellent overview of the current state of the field. In particular Fig 1 is very useful at summarising the different classess of microbiome based therapeutics currently being explored. The review unsurprisingly focuses a lot on FMT discussing it’s current application and clinical trials using FMT. But also contains some discussion of therapies beyond FMT. I did feel some discussion of bacteriophage was missing, as far as I can see it wasn’t even mentioned! I did enjoy this quote from the end, basically more mulit-omics!
“Given the marked genomic variation in bacterial strains that constitute the microbiota and our incomplete understanding of their metabolism and cooperativity in complex populations, advances in this field will require the type of curiosity-driven research that occurs in academic laboratories and that focuses on the microbiology, metagenomics, biochemistry, metabolomics and ecology of symbiotic bacterial populations.“
A few other reviews/comments/highlights that stood out to me recently
Clostridioides difficile toxins: mechanisms of action and antitoxin therapeutics – Kordus et al. Nature Reviews Microbiology. Published Jan 2022.
Mass spectrometry-based metabolomics in microbiome investigations – Bauermeister et al. Nature Reviews Microbiology. Published Sept 2021.
The Role of Dietary Interventions in The Regulation of Host-Microbe Interactions – Li et al. Frontiers in Cellular & Infection Microbiology. Pubflished Feb 2022.
As part of my research I’ve been involved with several studies of COVID-19 including in long COVID (LC). During the last few weeks there have been several impactful articles on LC published and pieces in The Guardian and NYT. I wanted to compare and contrast two of these and highlight some interesting findings.
To begin, what is often called long COVID in the media is also called post-acute sequelae of COVID-19 (PASC), post-acute COVID-19 syndrome, or post COVID-19 condition. It seems to affect ~5 – 30% of patients depending on the cohort and is not associated with severity, nor is it a post-intensive care syndrome (i.e. these aren’t a result of an extended stay in the ICU). The World Health Organisation provided a clinical definition of post-COVID-19 condition in October
“Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms and that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, cognitive dysfunction but also others and generally have an impact on everyday functioning. Symptoms may be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms may also fluctuate or relapse over time.” – WHO
First up Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection – Nature Immunology.
- Sampled up to 8 months post infection
- Very strong study design with multiple controls
- Unexposed healthy controls
- individuals who had COVID-19 but did not develop LC
- Individuals who had been infected with a different human coronavirus.
- Assessed 28 analytes in the serum including six proinflammatory cytokines & flow cytometry to measure multiple immune cell types.
Some of the serum analytes were significantly increased in both the LC and matched controls who did not develop LC indicating that the effect of COVID-19 on the immune system persists but is not necessarily associated with LC.
They built a classification model to determine an optimal set of features predictive of LC. I like the idea but their sample size is way too limited for this type of machine learning IMO.
Overall – Very strong study design and methodology but lack of some more global analyses left me wanting.
Second is Long-term perturbation of the peripheral immune system months after SARS-CoV-2 infection – BMC Medicine
- Sampled up to 6 months post infection
- Good study design, not as strong in terms of controls as the above.
- Unexposed healthy controls
- Individuals who had COVID-19 but did not develop LC
- Performed a deeper multi-omics analysis incorporating RNASeq, Flow cytometry and serology
Found a large degree of changes in both blood gene expression, and immune cell frequency/activation that were present in all patients post-COVID-19 irrespective of if they developed LC. They found that LC was associated with changes in a number of genes related to platelet function.
Overall – Global analyses were strong, but lacked some of the additional controls that the first study had.
When comparing and contrasting between these two studies they agree that differences are present in the immune system following COVID-19, and that most/all of these changes are not associated with LC. The Nature Immunology study points to changes in myeloid cell activation as being associated with LC, but the BMC Medicine study doesn’t reproduce this. The BMC Med study finds changes in platelets associated with LC in their gene expression data but unfortunately neither study directly measures platelets as they focus on the PBMC fraction (no platelets/erythrocytes).
Finally, I wanted to highlight a study published shortly after the two above. Multiple Early Factors Anticipate Post-Acute COVID-19 Sequelae – Cell. This study is a little different in that it followed 309 patients (from two independent cohorts) from diagnosis through recovery performing a range of multi-omics analyses.
They identifiedy four risk factors for developing LC at time of COVID-19 dianosis – Type 2 diabetes, SARS-CoV2 RNAemia, Epstein-Barr virius viremia and specific autoantibodies, and then subgrouped patients by these for analysis post COVID-19. Notably, they sampled only to 2-3 months post infection which if the studies above are to be believed is too early to detect any of the immunological changes associated with LC. This article is only currently available as a journal pre-proof (accepted at Cell, but needs to go through production I believe) and it seems to be missing some of the figure legends (I’m sure this will be fixed when fully published). This combined with the very different study design makes it difficult to directly compare to the studies above. There is a very strong focus here on comparing among patient groups they define rather than just LC vs matched controls that did not develop LC.
Overall – A methodologically excellent study, but I wish the authors did more to allow for more direct comparisons between this study and other work.
Also recently published.
Post-acute neurological consequences of COVID-19: an unequal burden – Nature Medicine
Long COVID in children – The Lancet Child Adolescent Health
New Research Hints at 4 Factors That May Increase Chances of Long Covid – The New York Times
My favorite recent cover goes to the Biram et al. article in Immunity which found that germinal centre formation can be disrupted when infected with a second pathogen.
Host-fungi interactions are clearly very important but have long been ignored so happy to see some mechanisms being profiled. This article demonstrates that sensing fungi can lead to altered neutrophil activity. I wonder does this extend to fungi in the microbiome (The authors here used a Candida model).
I’m always a sucker for a multi-omics paper. The biology here is obviously very cool for studying HIV infection but from a methods point of view it’s pretty amazing that they can get surface protein expression, cellular transcriptome, HIV-1 RNA, and TCR sequences within the same single cell.
Bioinformatic methods corner
An implementation of popular batch correction technique COMBAT for cytometry data. This is potentially a game changer for large flow cytometry or other datasets. COMBAT is so useful for RNASeq, and I’m pretty excited to try this out! Find more info at their Github
Reports on development of SameStr, a tool for identifying shared strains across metagenomes through SNVs in marker genes. Seems like a useful tool (although I’d love one that doesn’t need a reference db :D). Not sure I’ve ever seen someone related strains from metagenomics to a host phenotype in a systematic way but this gives me an idea.
Some love for viral metagenomes. This tools looks useful. Seems to go beyond just implementing command line things in a user-friendly way. The macro- and micro-diversity estimates look interesting, not sure I’ve seen that in a viral metagenome paper (Although I’ve been out of that game for ~4 years now).
Carbohydrate-active enzymes (CAZymes) in the gut microbiome – Nature Reviews Microbiology
Other papers that caught my eye recently
First wanted to shout out to the cover of Cell last week. Inspired by one of my favourite pieces of art The Great Wave by Japanese artist Hokusai. Love it! It references a study of a COVID outbreak in a vaccinated community published by Siddle et al.
Fascinating study on how experiences in your environment shape the gut microbiota.
- Housing mice in an enriched environment changes the gut microbiota
- An intact gut microbiota is necessary for enrichment-driven cortical plasticity
- Short-chain fatty acids modulate microglia morphology and visual cortical plasticity
- The pro-plasticity phenotype of enriched mice is transferred by fecal transplant
Long-term cardiovascular outcomes of COVID-19 – Nature Medicine.
Fascinating study. A little outside my expertise but will be very interested to see if this is reproduced by others. It’s could be a potent argument to get vaccinated.
“Here we used national healthcare databases from the US Department of Veterans Affairs to build a cohort of 153,760 individuals with COVID-19, as well as two sets of control cohorts with 5,637,647 (contemporary controls) and 5,859,411 (historical controls) individuals, to estimate risks and 1-year burdens of a set of pre-specified incident cardiovascular outcomes“
“We show that, beyond the first 30 d after infection, individuals with COVID-19 are at increased risk of incident cardiovascular disease spanning several categories, including cerebrovascular disorders, dysrhythmias, ischemic and non-ischemic heart disease, pericarditis, myocarditis, heart failure and thromboembolic disease. These risks and burdens were evident even among individuals who were not hospitalized“
The vaccine technology being developed due to the pandemic is very exciting this is prime example!
“We show that single-dose intranasal immunization, particularly with chimpanzee Ad-vectored vaccine, is superior to intramuscular immunization in induction of the tripartite protective immunity consisting of local and systemic antibody responses, mucosal tissue-resident memory T cells and mucosal trained innate immunity. We further show that intranasal immunization provides protection against both the ancestral SARS-CoV-2 and two VOC, B.1.1.7 and B.1.351“
Sounds like a major advacement in spatial omics tech! Very excited to see where this goes. Combining this with something like spatial 10X RNASeq and spatial mass spec would have some great applications in studying host-microbe interactions.
“This method resolved spatially distinct and cell-type-specific chromatin modifications“
“Spatial-CUT&Tag adds a new dimension to spatial biology by enabling the mapping of epigenetic regulations broadly implicated in development and disease“
Very cool resource for studying host-pathogen interactions. I’m not sure I’ve ever heard of a collaborative cross mouse panel before, but that says more about me I think.
“We leveraged the genetically diverse Collaborative Cross (CC) mouse panel in conjunction with a library of Mtb mutants to create a resource for associating bacterial genetic requirements with host genetics and immunity. We report that CC strains vary dramatically in their susceptibility to infection“
“many virulence pathways are only required in specific host microenvironments, identifying a large fraction of the pathogen’s genome that has been maintained to ensure fitness in a diverse population“
” In this review, we advocate for longitudinal multiomics data collection and demonstrate how incorporating knowledge gleaned from microbial community ecology and computational methods developed for microbiome research can serve as an anchor to advance the study of human milk and its many components as a “system within a system.”“
Dendritic cells are my favourite cell type so I couldn’t not highlight this article finding that a subset of B cells copy DCs
• Genome-wide transcriptome analysis of dengue vaccine-elicited immune responses
• A temporality of changes in lncRNA, splicing, and gene expression patterns
• Genes strongly enriched for pathways involved in antiviral innate immunity
• Cell-type-related modules exhibit a significant correlation with antibody titers
“These data provide insights into the early determinants of the variable immune response to the vaccine, highlighting the significance of splicing and isoform-level gene regulatory mechanisms in defining vaccine immunogenicity.”
This is a blog I’m putting together Highlighting new research in host – microbe interactions. Partially to keep me honest and make sure I actually keep up with new literature (I’m a post-doctoral fellow working in Host-microbe interaction research)
Not 100% sure yet what format I want to try so it might change a bit in the first few weeks but lets see how it goes!